Biomarkers in Metastatic Cholangiocarcinoma
Recommendations for conducting molecular testing and biopsies to learn more about patients who present with metastatic cholangiocarcinoma.
Afsaneh Barzi, MD, PhD: I gave a few examples of targeted therapies finding their way into the landscape of cholangiocarcinoma. Therefore molecular testing has become a paradigm for evaluation of patients with cholangiocarcinoma. A variety of targeted therapies have FDA approval in the setting as mentioned: ivosidenib, pemigatinib and infigratinib are examples of that. Other targeted therapies, although not FDA approved, they do have basically data to support them, such as BRAF mutations. There are also tumor agnostic therapies such MSI [microsatellite instability] and NTRK fusions that, considered together, provide the rationale for looking for these changes in this patient population. The questions are: when to test, what to test, what to look for in a test, and what platform of testing is the most appropriate? I do believe that in patients who are fit, upfront testing is the best strategy. Part of the reason for that is No. 1, there are clinical trials in the upfront setting that we may be able to get these patients on. However, the more important thing is that this can be a rapidly progressive disease with a rapid decline in the patient condition. If they’re discovered to have disease progression, the time that is spent to identify any marker in that window can potentially be detrimental to the patient condition and the opportunity for use of a targeted therapy. Therefore, earlier testing for better identification of the potential biomarkers for therapy is recommended in this patient population.
The other problem with this patient population is sometimes the biopsy specimen that we have on these patients is very small. I may submit tissue that I have that’s obtained through the diagnostic process, then the result I get is that the tissue is inadequate for NGS [next-generation sequencing] or any other molecular testing that we are interested in. If the patients are in good shape, that provides the opportunity for repeat biopsy, better testing, and gives us a window of opportunity to identify the right patient for the right treatment. The other question is, what kind of testing should we do? I know many of us in the oncology community have been users of next-generation sequencing, which in my opinion is an appropriate platform to use in this patient population given the multitude of the targets. The fact that tissue may not be adequate to do test by test by test, the thing that we must to be careful about is we have to look at the results of the molecular or NGS testing very carefully. Usually when we get the results, on the front page is a summary of the findings.
The real question is not what was found on the tissue, but also what wasn’t found. Usually in the back of the report there is a table that says whether the tissue was inadequate, or the amount and the quantity of DNA, or the technology was inadequate for testing specific targets. That’s important to know. An example is that if you’re looking for FGFR fusions, which are the biomarker for infigratinib and pemigatinib, and you look back and it says they could not verify the presence of FGFR2 fusions, then not seeing that result on the front page doesn’t mean the patient doesn’t have it. It only means we need to dig deeper to identify these patients and be certain that a negative result is a true negative result. Another thing is the use of liquid biopsies and whether there’s a justification for using liquid biopsy in this setting. Although liquid biopsies are good and well validated for mutations, their ability to detect other genomic alterations, such as fusions or rearrangements, is very limited. Relevant to the FGFR2 fusions, there was an abstract that was presented at ASCO [American Society of Clinical Oncology annual meeting] 2019 that looked at the Guardant360 test for detection of an FGFR alteration in the urethral cancer population. The Guardant360 test was correlated with the tissue testing. Only 25% of the patients who on the tissue had FGFR alterations were identified to have FGFR fusions by liquid biopsies.
Although these tests are evolving and are getting better, purely relying on liquid biopsies for this unique genomic alteration should be avoided. The other caveat with the liquid biopsies is the timing of the test. Testing the patient at the time of their best response to therapy isn’t optimum for identifying the cell-free DNA. You can imagine that if a patient had responded to therapy, the shedding of the tumor or the volume of the DNA in the circulating blood is less, and therefore the likelihood of finding something that would be guiding the treatment goes down. To summarize, I think NGS is the standard testing. Testing should be done on the tissue, and liquid biopsies should be avoided for the most part. If for any reason there is a patient for whom it’s difficult to obtain a repeat biopsy and we’re relying on liquid biopsy, we should do the testing at a time when the patient is progressing or has maximum quantity of the tumor to reduce the chance of not detecting adequate DNA, and as a result, the changes we’re looking for to guide our therapy.
Transcript edited for clarity.
Case: A 75-Year-Old Man with Metastatic Cholangiocarcinoma
May 2021
Initial presentation
- A 75-year-old man presents with abdominal pain and weight loss.
Clinical workup
- History of hepatitis B infection more than 10 years ago and hypertension which is controlled with medication
- Blood work reveals serum levels of CA 19-9 (1200 U/ml), bilirubin 1.5 mg/dL, ALT 250 U/L, AST 95 U/L
- MRI imaging shows multiple liver masses
- Histopathological examination identifies adenocarcinoma with primarily mucin-producing glands
- Patient is identified to have intrahepatic cholangiocarcinoma (iCCA).
- CBC is unremarkable (absolute neutrophil count 3,500/mm3, platelets 300,000/ml, hemoglobin 10.1 g/dL)
- ECOG PS is 1 and the patient is in good health.
- Patient is referred to oncologists for next steps and is started on treatment with gemcitabine and cisplatin in June 2021.
Sept. 2021
- Patient is experiencing grade 2-3 neutropenia and fatigue and the oncologist has adjusted the dose to reduce toxicities with chemotherapy.
